Methods and compositions for increasing solubility of azole drug compounds that are poorly soluble in water

ABSTRACT

The combination of any two of a polyol, a polyol ether, and a low carbon organic alcohol provides a synergistic effect on the solubility of azole compounds, such as metronidazole, in aqueous fluid.

This application is a continuation of U.S. patent application Ser. No.12/012,413, filed Feb. 2, 2008, now U.S. Pat. No. 7,893,097.

FIELD OF THE INVENTION

The present invention pertains to the field of increasing solubility ofchemical compounds in aqueous fluids.

BACKGROUND OF THE INVENTION

Many chemical compounds, particular chemical compounds that are usefulin pharmacologic applications, are poorly soluble in water. Such drugsmay be classified according to USP-NF as being sparingly soluble,slightly soluble, very slightly soluble, or insoluble in water. Many ofthese compounds are also poorly soluble in oils. An example of such achemical compound includes the azole family of drugs, which familyincludes metronidazole, fluconazole, ketoconazole, itraconazole,miconazole, dimetridazole, secnidazole, ornidazole, tinidazole,carnidazole, and panidazole.

In many situations, such drugs may be formulated as a suspension, inwhich case the lack of solubility of the drug in water and inpharmaceutical oils does not typically have a negative impact onbioavailability. However, in situations where a solution of the drug isdesired, or where an emulsion containing the drug in solution either inthe hydrophilic or lipophilic phase of the emulsion is desired, the lackof solubility of the drug in water and oils provides a significantobstacle to obtaining desired concentrations of the drug.

The need to increase the aqueous solubility of poorly water solubledrugs that are also poorly soluble in oils is especially critical whenformulating an emulsion, such as a topical cream, lotion, or ointment,containing such a drug. In this case, in order to obtain a sufficientlyhigh concentration of the drug in the emulsion formulation as a whole,the concentration of the drug in the aqueous phase must be sufficientlyelevated to overcome the lack of partitioning of the drug into the oilphase.

Metronidazole is an antimicrobial drug that is administered systemicallyfor treatment of infections with anaerobic bacteria and protozoans, suchas Trichomonas, Entamoeba, and Giardia. It is also used topically totreat bacterial vaginosis and various forms of acne, including acnerosacea. The aqueous solubility of metronidazole in water at roomtemperature is only about 0.87% w/w. Additionally, physically stablesolutions of metronidazole in water that can withstand exposure to coldtemperatures encountered during shipping are limited to about 0.7% w/wmetronidazole. However, for many topical applications, a concentrationof 1.0% or higher is desired.

The lack of solubility of such drugs, and the inability to obtainsufficiently high concentrations of drugs in solution inpharmaceutically acceptable carriers, is a serious problem in theformulation of topical therapeutic products for the treatment of medicalconditions affecting the skin or mucosa. Such lack of solubility isadditionally a concern in the formulation of medications for parenteraladministration and for oral liquids that are often used for children andgeriatric patients. Accordingly, a significant need exists for a methodto increase the solubility of drugs that are poorly soluble in water,and especially those, like azole drugs such as metronidazole, that arealso poorly soluble in pharmaceutical oils.

DESCRIPTION OF THE INVENTION

It has been unexpectedly discovered that the combination of any two of apolyol, a polyol ether, and a low carbon organic alcohol provides asynergistic effect that produces an increase in the aqueous solubilityof poorly water soluble compounds such as drugs, including poorly watersoluble compounds, such as azole drugs.

As used herein, the term “poorly soluble” when referring to a chemicalcompound in relation to its solubility in water or an oil means achemical compound that is sparingly soluble, slightly soluble, veryslightly soluble, or insoluble in water or an oil, as defined in U.S.Pharmacopeia and National Formulary (USP-NF). According to thisdefinition, solubility is stated in terms of the parts of the solventneeded to dissolve one part of the solute. A compound that is sparinglysoluble in a particular solvent, such as water, requires 30-100 parts ofthe solvent to dissolve one part of the compound. A compound that isslightly solvent requires 100-1000 parts of the solvent. A compound thatis very slightly soluble requires 1000-10,000 parts of the solvent. Acompound that is insoluble requires more than 10,000 parts of thesolvent to dissolve one part of the solute.

As used herein, the term “polyol” is synonymous with “polyhydricalcohol” and refers to an alcohol that contains more than one hydroxylgroup. Examples of polyols include polyether glycols, propylene glycol,and sugar alcohols.

As used herein, the term “polyol ether” refers to an alcohol thatcontains more than one hydroxyl group and an ether group. Examples ofpolyol ethers include diethylene glycol monoethyl ether (ethoxydiglycol)(Transcutol®, Gattefosse Corporation, Paramus, N.J.), ethers ofpentaerythritol, ethers of alkylene glycol, ethers of a fatty alcohol,and ethers of a sugar.

As used herein, the term “low carbon organic alcohol” refers to analcohol having the formula RCH₂OH, wherein R is either H or is astraight or branched alkyl chain of 1 to 7 carbons, or having a ringstructure directly connected to a hydroxyl group or connected to ahydroxyl group by a carbon. Examples of low carbon organic alcoholsinclude alkyl and aryl alcohols such as ethyl alcohol, propyl alcohol,isopropyl alcohol, phenol, and benzyl alcohol.

An example of such a poorly water soluble compound that is poorlysoluble in pharmaceutical oils is the drug metronidazole, a member ofthe azole family of medications. This drug is utilized as anillustration of the invention. However, it will be understood that thedescription of the invention herein pertains not just to metronidazolebut to all members of the azole family of medications, for example,fluconazole, ketoconazole, itraconazole, miconazole, dimetridazole,secnidazole, ornidazole, tinidazole, carnidazole, and panidazole.

In accordance with the invention, a polyol and a polyol ether, a polyoland a low carbon organic alcohol, a polyol ether and a low carbonorganic alcohol, or a polyol, a polyol ether, and a low carbon organicalcohol are combined in an aqueous fluid with a poorly water solublechemical azole compound, such as metronidazole to form an aqueoussolution. The total concentration of the polyol and the polyol ether,the polyol and the low carbon organic alcohol, the polyol ether and thelow carbon organic alcohol, or the polyol, the polyol ether, and the lowcarbon organic alcohol that is combined in the aqueous fluid is thatwhich is sufficient to provide a synergistic increase in the solubilityof the azole chemical compound in the aqueous fluid in the absence ofany two or more of a polyol, a polyol ether, and a low carbon organicalcohol.

The absolute and relative concentrations of the polyol, polyol ether,and low carbon organic alcohol in the aqueous fluid may be varied, ifdesired, in order to obtain a particular increase in solubility of theazole compound in the aqueous fluid. It is expected, however, that anyamount and any ratio of two or more of a polyol, polyol ether, and lowcarbon organic alcohol will result in a synergistic increase insolubility of azole compounds in the mixed solvent system compared tothe solubility of the azole compounds in an aqueous fluid lacking two ormore of a polyol, a polyol ether, and a low carbon organic alcohol.

The aqueous fluid may contain, in addition to the above components,additional components such as, but not limited to, additional solubilityenhancing agents such as one or more of a cyclodextrin, niacin, andniacinamide, gelling agents such as a carbomer or a cellulosic polymer,preservatives, chelating agents, pH adjusting agents, and buffers.

The aqueous solution of the invention may constitute the internalaqueous phase of a water-in-oil emulsion or the external aqueous phaseof an oil-in-water emulsion. Methods of making such emulsions are wellknown in the art.

The solutions of the invention, including gels, may be used for thetopical treatment of dermatologic or mucosal disorders that areresponsive to therapy with azole compounds such as metronidazole. Inaccordance with the method of treatment of the invention, a stableaqueous solution as described herein containing an azole compound andtwo or more of a polyol, a polyol ether, and a low carbon organicalcohol is topically applied to skin or mucosal surfaces in need of suchtherapy. Examples of disorders that are suitably treated in accordancewith the invention include inflammatory lesions on skin or mucosa, suchas oral or vaginal mucosa, diabetic foot ulcers, and certain infectiousdiseases that are responsive to topical therapy. A particular disorderthat may be treated with the method of the invention is rosacea, alsoknown as acne rosacea.

Preferably, the dissolved concentration of the azole compound in thepharmaceutical formulation of the invention is sufficient so thatapplication once daily is effective to ameliorate the disorder. Forexample, with metronidazole, concentrations of about 1% or higherprovide effective treatment when applied only once daily. Atconcentrations below 1.0%, it is recommended to apply a metronidazoleformulation at least twice daily. The solution containing metronidazoleor other azole compound is applied on a daily basis, one or more timesper day, for a time sufficient to produce an amelioration or a cure ofthe disorder. In certain chronic disorders, the solution may be appliedone or more times daily for a prolonged period to prevent worsening ofthe disorder.

The invention is further illustrated in the following non-limitingexamples. In the examples, propylene glycol is utilized as arepresentative polyol, Transcutol® is utilized as a representativepolyol ether, benzyl alcohol is utilized as a representative low carbonorganic alcohol, and metronidazole is utilized as a representative azolechemical compound. It is understood, however, that other polyols, polyolethers, low carbon organic alcohols, and azole compounds may besubstituted in place of the exemplified propylene glycol, Transcutol®,benzyl alcohol, and metronidazole.

Example 1 Procedure for Determining Solubility of Metronidazole

In the Examples that follow, solubility of metronidazole was determinedas follows.

An appropriate amount of each vehicle component was weighted into a 20ml scintillation vial and the components were shaken until a clearsolution was obtained. Metronidazole was then added to the solution andthe vials were shaken overnight at room temperature to obtain asaturated solution of metronidazole. The solution was filtered to removeany undissolved metronidazole and the concentration of metronidazoledissolved in the solution was determined by HPLC. The solutions werephysically stable at room temperature for at least two weeks, with noprecipitation formation.

Example 2 Solubility of Metronidazole in Single Vehicles

The procedure of Example 1 was performed to determine the solubility ofmetronidazole in a single vehicle solvent selected from water,ethoxydiglycol, benzyl alcohol, and propylene glycol. The results areshown below in Table 1.

TABLE 1 Solvent Metronidazole Solubility % w/w Water 0.87 Ethoxydiglycol2.47 Benzyl Alcohol 6.23 Propylene Glycol 1.88

Example 3 Solubility of Metronidazole in Multiple Vehicle SystemContaining Water, a Polyol, a Polyol Ether, and a Low Carbon OrganicAlcohol

The procedure of Example 1 was performed to determine the solubility ofmetronidazole in a multiple vehicle solvent system containing water,ethoxydiglycol, benzyl alcohol, and propylene glycol. The composition ofthe solvent system is shown below in Table 2.

TABLE 2 Components Amount % w/w Ethoxydiglycol 29.8 Benzyl Alcohol 5.0Propylene Glycol 10.0 Water 55.2

Based on the solubility of metronidazole in each component of themulti-component vehicle system, the anticipated solubility ofmetronidazole in this vehicle was calculated to be 1.716% w/w. Thecalculations are shown in Table 3, where the solubility of eachcomponent in isolation times the concentration in the vehicle blendprovides the anticipated (additive or calculated) solubility.

TABLE 3 Metronidazole solubility in Fractional individual AnticipatedComponent Amount component % w/w solubility % w/w Ethoxydiglycol 0.2982.47 0.736 Benzyl Alcohol 0.050 6.23 0.312 Propylene 0.100 1.88 0.188Glycol Water 0.552 0.87 0.480 Total 1.000 1.716

Although, as shown in Table 3, the anticipated solubility ofmetronidazole in the multiple vehicle system was calculated to be 1.716%w/w, the actual solubility of metronidazole in this multi-componentvehicle system was experimentally determined, by HPLC, to be 2.54% w/w,see Table 6, Blend #1, in Example 5 below. The solubility ofmetronidazole in the multi-component vehicle system was 48.5% higherthan expected if the contribution to solubility by each of thecomponents was additive. Thus, the results of this study establish thatthe combination of water, polyol, polyol ether, and low carbon organicalcohol provides a synergistic effect on the solubility of metronidazolein an aqueous vehicle.

Example 4 Solubility of Metronidazole in Multi-Component Vehicle SystemContaining Water, a Polyol, a Polyol Ether, and a Low Carbon OrganicAlcohol

The procedure of Example 3 was repeated except that the concentration ofbenzyl alcohol in the aqueous fluid was reduced by 50% and theconcentration of water in the fluid was increased accordingly. Thecomposition of the solvent system is shown in Table 4.

TABLE 4 Components Amount % w/w Ethoxydiglycol 29.9 Benzyl Alcohol 2.5Propylene Glycol 10.1 Water 57.5

Based on the solubility of metronidazole in each component of themultiple vehicle system, the anticipated solubility of metronidazole inthis system was calculated to be 1.582% w/w. The calculations are shownin Table 5.

TABLE 5 Metronidazole solubility in Fractional individual AnticipatedComponent Amount component % w/w solubility % w/w Ethoxydiglycol 0.2992.47 0.739 Benzyl Alcohol 0.025 6.23 0.156 Propylene Glycol 0.101 1.880.190 Water 0.575 0.87 0.500 Total 1.000 1.584

In the solution containing the components shown in Table 4, thesolubility of metronidazole in the multi-component vehicle system wasexperimentally determined, by HPLC, to be 2.07% w/w, see Table 6, Blend#2, in Example 5 below. The solubility of metronidazole in thismulti-component vehicle system was 31.0% higher than expected if thecontribution to solubility by each of the components was additive.

Example 5 Solubility of Metronidazole in a Variety of Concentrations ofthe Multi-Component Solvent System

The procedure of Example 1 was utilized to create a variety ofmulti-component solvent systems containing water, a polyol, a polyolether, and a low carbon organic alcohol. The anticipated calculatedsolubility of metronidazole in each system was calculated and the actualsolubility of metronidazole in each system was determined by HPLC asdescribed in Example 1. Blends #1 and 2 are the solvent systems ofExamples 3 and 4, respectively. The results are shown in Table 6.

TABLE 6 Theoret- Actual Solub- ical Solub- ility Benzyl Propy- Solub-ility In- Blend Trans- alco- lene ility (% crease # Water cutol ® holglycol (% w/w)¹ w/w)² %³ 1 55.2 29.8 5.0 10.0 1.71 2.54 48.5* 2 57.529.9 2.5 10.1 1.58 2.07 31.0* 3 60.0 30.0 0.0 10.0 1.45 1.66 14.5* 465.1 29.9 0.0 5.0 1.4 1.48 5.7 5 65.0 30.0 5.0 0.0 1.62 2.27 40.1* 671.0 29.0 0.0 0.0 1.33 1.35 1.5 7 73.1 16.9 0.0 10.0 1.24 1.22 (1.6) 874.1 16.0 5.0 5.0 1.44 1.96 36.1* 9 74.5 12.9 2.5 10.1 1.31 1.54 17.6*10 74.9 23.0 2.1 0.0 1.35 1.66 23.0* 11 81.4 11.1 2.5 5.0 1.23 1.4316.3* 12 83.9 1.1 5.1 10.0 1.26 1.72 36.5* 13 84.9 0.0 5.1 10.0 1.241.66 33.9* 14 89.0 11.0 0.0 0.0 1.04 1.01 (2.9) 15 89.9 0.0 0.0 10.10.97 0.93 (4.1) 16 91.5 3.4 5.1 0.0 1.2 1.56 30.0* 17 92.5 0.0 2.5 5.11.05 1.20 14.3* 18 95.0 0.0 0.0 5.0 0.92 0.91 (1.1) 19 95.0 0.5 4.5 0.01.12 1.44 28.6* 20 97.6 0.0 2.4 0.0 1.00 1.09 9.0 ¹Theoretical(anticipated) solubility is based on the assumption that each solvent'scontribution to overall solubility is additive and is calculated fromthe determined solubility of metronidazole due to each component asshown in Table 1 in Example 2 ²Actual solubility of metronidazole wasobtained by HPLC analysis ³Actual solubility minus theoreticalsolubility divided by theoretical solubility and multiplied by 100.*Solubility increase or (decrease) greater than +/− 10% is considered tobe significant

The data in Table 6 establishes the synergism obtained by combination ofany two of a polyol, a polyol ether, and a low carbon organic alcohol.The highest percentage increases in solubility were obtained in solventsystems that included a low carbon organic alcohol. No increase insolubility above the calculated solubility was obtained when utilizing asolvent system containing water and only one other solvent.

Example 6 Metronidazole 1.5% Gel

An exemplary gel pharmaceutical composition containing metronidazole ata concentration of 1.5% w/w was produced by combining the followingcomponents, as shown below in Table 7.

TABLE 7 Components % w/w Metronidazole 1.50 Propylene glycol 5.00Niacinamide 3.00 Beta-Cyclodextrin 1.00 Methylparaben 0.15 Propylparaben0.05 EDTA disodium 0.05 Transcutol ® P 15.00 Benzyl alcohol 1.00Carbopol ® Ultrez 10 0.50 25% Triethanolamine q.s. pH 6.0 10% HClsolution q.s. pH 6.0 Purified water q.s. 100.00

The gel composition was made by combining metronidazole, propyleneglycol, niacinamide, beta-cyclodextrin, methylparaben, propylparaben,EDTA disodium, Transcutol® P, and benzyl alcohol in a manufacturingvessel. These components were mixed while heating to 65° C. until aclear solution was obtained. After removal from the heat source, thegelling agent, Carbopol® Ultrez 10 (Lubrizol Corp., Wickliffe, Ohio) wasadded with continuous mixing until dispersed into the mixture. Mixingwas continued until a homogenous gel was formed and the system reachedroom temperature. The pH was then adjusted to 6.0+/−0.3 withtriethanolamine or HCl solution.

Example 7 Metronidazole 1.25% and 1.5% Gels

Exemplary gel pharmaceutical compositions containing metronidazole at aconcentration of 1.25% w/w and 1.5% w/w were produced according to themethod of Example 6 by combining the following components, as shownbelow in Tables 8 and 9, respectively. The solutions were determined tobe stable with no evidence of precipitate formation following storage atroom temperature for two weeks or at a temperature of 5° C. for oneweek.

TABLE 8 Components % w/w Metronidazole 1.25 Propylene glycol 5.00Methylparaben 0.15 Propylparaben 0.05 EDTA sodium 0.05 Ethoxydiglycol25.00 Benzyl alcohol 1.00 Carbopol ® Ultrez 10 0.50 25% Triethanolamineq.s. pH 6.0 10% HCl solution q.s. pH 6.0 Purified water q.s. 100.00

TABLE 9 Components % w/w Metronidazole 1.50 Propylene glycol 10.00Methylparaben 0.15 Propylparaben 0.05 EDTA sodium 0.05 Ethoxydiglycol25.00 Benzyl alcohol 2.00 Carbopol ® Ultrez 10 0.50 25% Triethanolamineq.s. pH 6.0 10% HCl solution q.s. pH 6.0 Purified water q.s. 100.00

Example 8 Metronidazole 1.25% and 1.5% Gels

Exemplary gel pharmaceutical compositions containing metronidazole at aconcentration of 1.25% w/w and 1.5% w/w were produced according to themethod of Example 6 by combining the following components, as shownbelow in Tables 10 and 11, respectively. The solutions were determinedto be stable with no evidence of precipitate formation following storageat room temperature for two weeks or at a temperature of 5° C. for oneweek.

TABLE 10 Components % w/w Metronidazole 1.25 PEG 400 5.00 Methylparaben0.15 Propylparaben 0.05 EDTA sodium 0.05 Ethoxydiglycol 35.00 Ethanol3.00 Carbopol ® Ultrez 10 0.50 25% Triethanolamine q.s. pH 6.0 10% HClsolution q.s. pH 6.0 Purified water q.s. 100.00

TABLE 11 Components % w/w Metronidazole 1.50 Hexylene glycol 5.00Methylparaben 0.15 Propylparaben 0.05 EDTA sodium 0.05 Ethoxydiglycol35.00 Ethanol 3.00 Carbopol ® Ultrez 10 0.50 25% Triethanolamine q.s. pH6.0 10% HCl solution q.s. pH 6.0 Purified water q.s. 100.00

Various modifications of the above described invention will be evidentto those skilled in the art. It is intended that such modifications areincluded within the scope of the following claims.

The invention claimed is:
 1. A method for treating a dermatologic ormucosal disorder that is responsive to treatment with an azole compoundcomprising applying to the skin or mucosa of an individual sufferingfrom said disorder a pharmaceutical formulation comprising water,metronidazole at a concentration between 1.25% and 1.5%, and at leasttwo of a polyol, a polyol ether, and a low carbon organic alcohol. 2.The method of claim 1 wherein the formulation is applied one or moretimes daily for a duration sufficient to ameliorate the disorder.
 3. Themethod of claim 1 wherein the disorder is infectious.
 4. The method ofclaim 3 wherein, the infectious disorder is fungal.
 5. The method ofclaim 1 wherein the individual is human.
 6. The method of claim 1wherein the low carbon organic alcohol is benzyl alcohol.
 7. The methodof claim 6 wherein the benzyl alcohol comprises about 1% w/w of theformulation.
 8. The method of claim 7 wherein the benzyl alcoholcomprises about 2% w/w of the formulation.
 9. The method of claim 1wherein the polyol is propylene glycol.
 10. The method of claim 1wherein the polyol ether is an ether of an alkylene glycol.
 11. Themethod of claim 10 wherein the ether of the alkylene glycol ispolyethylene glycol.
 12. The method of claim 11 wherein the polyethyleneglycol is polyethylene glycol 400 (“PEG 400”).
 13. The method of claim 1wherein the water comprises about 55% or more w/w of the formulation.14. The method of claim 1 wherein the formulation comprises each of apolyol, a polyol ether, and a low carbon organic alcohol.